Explore the vast range of titles available.

Physically crosslinked hydrogels with thixotropic properties attract considerable attention in the biomedical research field because their self-healing nature is useful in cell encapsulation, as injectable gels, and as bioinks for three-dimensional (3D) bioprinting. Here, we report the formation of thixotropic hydrogels containing nanofibers of double-hydrophobic elastin-like polypeptides (ELPs). The hydrogels are obtained with the double-hydrophobic ELPs at 0.5 wt%, the concentration of which is an order of magnitude lower than those for previously reported ELP hydrogels. Although the kinetics of hydrogel formation is slower for the double-hydrophobic ELP with a cell-binding sequence, the storage moduli G′ of mature hydrogels are similar regardless of the presence of a cell-binding sequence. Reversible gel–sol transitions are demonstrated in step-strain rheological measurements. The degree of recovery of the storage modulus G′ after the removal of high shear stress is improved by chemical crosslinking of nanofibers when intermolecular crosslinking is successful. This work would provide deeper insight into the structure–property relationships of the self-assembling polypeptides and a better design strategy for hydrogels with desired viscoelastic properties.

L‐Asparaginase (ASP) is well‐known for its excellent efficacy in treating hematological malignancies. Unfortunately, the intrinsic shortcomings of ASP, namely high immunogenicity, severe toxicity, short half‐life, and poor stability, restrict its clinical usage. Poly(ethylene glycol) conjugation (PEGylation) of ASP is an effective strategy to address these issues, but it is not ideal in clinical applications due to complex chemical synthesis procedures, reduced ASP activity after conjugation, and pre‐existing anti‐PEG antibodies in humans. Herein, the authors genetically engineered an elastin‐like polypeptide (ELP)‐fused ASP (ASP‐ELP), a core‐shell structured tetramer predicted by AlphaFold2, to overcome the limitations of ASP and PEG‐ASP. Notably, the unique thermosensitivity of ASP‐ELP enables the in situ formation of a sustained‐release depot post‐injection with zero‐order release kinetics over a long time. The in vitro and in vivo studies reveal that ASP‐ELP possesses increased activity retention, improved stability, extended half‐life, mitigated immunogenicity, reduced toxicity, and enhanced efficacy compared to ASP and PEG‐ASP. Indeed, ASP‐ELP treatment in leukemia or lymphoma mouse models of cell line‐derived xenograft (CDX) shows potent anti‐cancer effects with significantly prolonged survival. The findings also indicate that artificial intelligence (AI)‐assisted genetic engineering is instructive in designing protein‐polypeptide conjugates and may pave the way to develop next‐generation biologics to enhance cancer treatment. Artificial intelligence is applied to design elastin‐like polypeptide (ELP) fused L‐asparaginase (ASP) (ASP‐ELP). ASP‐ELP features mitigated immunogenicity and toxicity, and enhanced pharmacokinetics and efficacy in treating hematologic malignancies. The unique thermosensitivity of ASP‐ELP leads to the in situ formation of a sustained release depot with zero‐order release kinetics, avoiding side effects associated with a transient release.

Successful nerve repair using bioadhesive hydrogels demands minimizing tissue–material interfacial mechanical mismatch to reduce immune responses and scar tissue formation. Furthermore, it is crucial to maintain the bioelectrical stimulation‐mediated cell‐signaling mechanism to overcome communication barriers within injured nerve tissues. Therefore, engineering bioadhesives for neural tissue regeneration necessitates the integration of electroconductive properties with tissue‐like biomechanics. In this study, we propose a stretchable bioadhesive based on a custom‐designed chemically modified elastin‐like polypeptides (ELPs) and a choline‐based bioionic liquid (Bio‐IL), providing an electroconductive microenvironment to reconnect damaged nerve tissue. The stretchability akin to native neural tissue was achieved by incorporating hydrophobic ELP pockets, and a robust tissue adhesion was obtained due to multi‐mode tissue–material interactions through covalent and noncovalent bonding at the tissue interface. Adhesion tests revealed adhesive strength ~10 times higher than commercially available tissue adhesive, Evicel®. Furthermore, the engineered hydrogel supported in vitro viability and proliferation of human glial cells. We also evaluated the biodegradability and biocompatibility of the engineered bioadhesive in vivo using a rat subcutaneous implantation model, which demonstrated facile tissue infiltration and minimal immune response. The outlined functionalities empower the engineered elastic and electroconductive adhesive hydrogel to effectively enable sutureless surgical sealing of neural injuries and promote tissue regeneration.

Design of reversible organelle‐like microcompartments formed by liquid–liquid phase separation in cell‐mimicking entities has significantly advanced the bottom‐up construction of artificial eukaryotic cells. However, organizing the formation of artificial organelle architectures in a spatiotemporal manner within complex primitive compartments remains scarcely explored. In this work, thermoresponsive hybrid polypeptide‐polymer conjugates are rationally engineered and synthesized, resulting from the conjugation of an intrinsically disordered synthetic protein (IDP), namely elastin‐like polypeptide, and synthetic polymers (poly(ethylene glycol) and dextran) that are widely used as macromolecular crowding agents. Cell‐like constructs are built using droplet‐based microfluidics that are filled with such bioconjugates and an artificial cytoplasm system that is composed of specific polymers conjugated to the IDP. The distinct spatial organizations of two polypeptide‐polymer conjugates and the dynamic assembly and disassembly of polypeptide‐polymer coacervate droplets in response to temperature are studied in the cytomimetic protocells. Furthermore, a monoblock IDP with longer length is concurrently included with bioconjugates individually inside cytomimetic compartments. Both bioconjugates exhibit an identical surfactant‐like property, compartmentalizing the monoblock IDP coacervates via temperature control. These findings lay the foundation for developing hierarchically structured synthetic cells with interior organelle‐like structures which could be designed to localize in desired phase‐separated subcompartments. Two elastin‐like polypeptide‐block‐polymer conjugates as building blocks for artificial organelles are individually encapsulated inside cytomimetic cell‐like microdroplets. Regulation of temperature enables dynamic assembly/disassembly and programmable position of organelle‐mimics in crowded medium, as well as rapid compartmentalization of hydrophobic coacervates from a monoblock ELP.

Protein‐polymer conjugates show improved pharmacokinetics but reduced bioactivity and tumor penetration as compared to native proteins, resulting in limited antitumor efficacy. To address this dilemma, genetic engineering of a body temperature‐responsive and matrix metalloproteinase (MMP)‐cleavable conjugate of interferon alpha (IFNα) and elastin‐like polypeptide (ELP) is reported with spatiotemporally programmed two‐step release kinetics for tumor therapy. Notably, the conjugate could phase separate to form a depot postsubcutaneous injection, leading to 1‐month zero‐order release kinetics. Furthermore, it could selectively be cleaved by MMPs that are overexpressed in tumors to release IFNα from ELP and thus to recover the bioactivity of IFNα. Consequently, it exhibits dramatically enhanced tumor accumulation, tumor penetration, and antitumor efficacy as compared to free IFNα in two mouse models of melanoma and ovarian tumor. These findings may provide an intelligent technology of thermoresponsive and protease‐cleavable protein‐polymer conjugates with spatiotemporally programmed two‐step release kinetics for tumor treatment. A body temperature‐responsive and matrix metalloproteinase (MMP)‐cleavable protein‐polymer conjugate of interferon alpha (IFNα)‐MMP substrate‐elastin‐like polypeptide in situ forms a depot upon subcutaneous injection, slowly releases into the circulation system, accumulates into tumors, cleaves into free IFNα and ELP(V) by matrix metalloproteinases in the tumor, and leads to not only the recovery of IFNα bioactivity but also the enhancement in tumor penetration and antitumor efficacy.

Nab‐paclitaxel (Abraxane), an albumin‐bound solvent‐free paclitaxel (PTX) formulation that takes advantage of the endogenous albumin transport pathway, is the current gold standard for treatment of solid tumors with PTX. However, nab‐paclitaxel has several limitations, including complex manufacturing, immunogenicity, slow drug‐release, and a narrow therapeutic window. Nevertheless, no other PTX formulation has gained the Food and Drug Administration approval since Abraxane's 18‐year reign. Addressing these concerns, herein, a PTX‐loaded nanoparticle of a recombinant polypeptide that—like nab‐paclitaxel—capitalizes on the long in vivo half‐life of albumin is reported. This genetically engineered nanoparticle packages PTX in the core of the nanoparticle and displays an albumin‐binding domain on the exterior of the nanoparticle. Upon in vivo administration, the drug‐loaded nanoparticle binds albumin with nanomolar affinity, and acquires an albumin‐corona, which eliminates the need to use exogenous albumin. The nanoparticles can be stored at subzero temperature as lyophilized powder without any cryoprotectants for upto a year and can be reconstituted on‐demand in aqueous buffer at high concentration, thus greatly simplifying formulation processes. These albumin‐binding nanoparticles improve the therapeutic window by at least twofold compared to nonalbumin‐binding counterpart and outperform nab‐paclitaxel in multiple murine tumor models, results that have been independently replicated by a contract research organization. Genetically engineered paclitaxel nanoparticles bind endogenous serum albumin post administration, leveraging albumin's long half‐life to improve circulation time, drug exposure, and therapeutic window. These albumin‐binding nanoparticles double the therapeutic window compared to nonalbumin‐binding counterparts and outperform nab‐paclitaxel in various murine tumor models, with results independently confirmed by a contract research organization.

Biomaterials can improve cancer immunotherapies by controlling their release and thereby optimizing their time‐dependent engagement of the immune system. In this study, an approach is described to control the release of a potent immunostimulant—CpG oligodeoxynucleotide—from a genetically‐encoded elastin‐like polypeptide (ELP) depot. A CpG‐binding ELP containing an oligolysine domain (ELP‐Lys12) is synthesized that electrostatically complexes CpG and formulate it with an excipient ELP. The ELP‐CpG complex retains the thermally responsive phase behavior of the parent ELP, transitioning into a viscous depot at body temperature. Stepwise addition of excipient ELP predictably changes ELP‐CpG transition temperature, depot dissolution kinetics, and retention of CpG within the depot. Mixtures of ELP‐Lys12, excipient ELP, and CpG undergo microphase separation, forming a porous, sponge‐like depot that contains tunable amounts of soluble CpG in the pores. In vivo, the modified formulations exhibit varying degrees of CpG retention over multiple weeks following a single intratumoral injection. Finally, by modifying the release kinetics of CpG, optimized ELP‐CpG achieves greater reduction of metastatic disease in a murine metastatic breast cancer model than soluble CpG. These results demonstrate that ELPs can be used to precisely tune the release kinetics of immunotherapies for better outcomes in the treatment of metastatic cancer. We show that intratumoral release of an immunotherapy—CpG —can be tuned with molecular precision by complexing it to an elastin‐like polypeptide (ELP). Injecting ELP‐CpG and an excipient ELP into tumors drives thermally‐triggered phase separation into a micro‐scale “sponge” depot that releases CpG at rates depending on the ELP composition, which correlates with control of metastatic breast cancer in mice.

Elastin-like polypeptides (ELPs) are thermally responsive biopolymers derived from natural elastin. These peptides have a low critical solution temperature phase behavior and can be used to prepare stimuli-responsive biomaterials. Through genetic engineering, biomaterials prepared from ELPs can have unique and customizable properties. By adjusting the amino acid sequence and length of ELPs, nanostructures, such as micelles and nanofibers, can be formed. Correspondingly, ELPs have been used for improving the stability and prolonging drug-release time. Furthermore, ELPs have widespread use in tissue repair due to their biocompatibility and biodegradability. Here, this review summarizes the basic property composition of ELPs and the methods for modulating their phase transition properties, discusses the application of drug delivery system and tissue repair and clarifies the current challenges and future directions of ELPs in applications.

Tumor necrosis factor alpha (TNF-α) was discovered more than a century ago, and its known roles have extended from within the immune system to include a neuro-inflammatory domain in the nervous system. Neuropathic pain is a recognized type of pathological pain where nociceptive responses persist beyond the resolution of damage to the nerve or its surrounding tissue. Very often, neuropathic pain is disproportionately enhanced in intensity (hyperalgesia) or altered in modality (hyperpathia or allodynia) in relation to the stimuli. At time of this writing, there is as yet no common consensus about the etiology of neuropathic pain - possible mechanisms can be categorized into peripheral sensitization and central sensitization of the nervous system in response to the nociceptive stimuli. Animal models of neuropathic pain based on various types of nerve injuries (peripheral versus spinal nerve, ligation versus chronic constrictive injury) have persistently implicated a pivotal role for TNF-α at both peripheral and central levels of sensitization. Despite a lack of success in clinical trials of anti-TNF-α therapy in alleviating the sciatic type of neuropathic pain, the intricate link of TNF-α with other neuro-inflammatory signaling systems (e.g., chemokines and p38 MAPK) has indeed inspired a systems approach perspective for future drug development in treating neuropathic pain.